Outline

Objective

Adenosine is increasingly release in metabolic stress conditions, like hypoxia or ischemia, and regulates many physiologic processes, e.g. aqueous humor secretion and intraocular pressure, via activation of four adenosin receptors (AR). We investigated the role of the adenosine system in the pathophysiology of pseudoexfoliation (PEX) syndrome, which is typically associated with anterior chamber hypoxia and elevated intraocular pressure.

Methods

Differential and subtractive gene expression analyses, Northern blots, RT-PCR, in situ hybridization and immunohistochemistry were applied to analyze the mRNA and protein expression of the four AR subtypes A1, A2A, A2B, and A3 in ocular tissues of patients with PEX syndrome, PEX glaucoma, primary open-angle glaucoma (POAG), angle-closure glaucoma (ACG), and normal control eyes. Adenosine levels were measured in the aqueous humor of patients with PEX syndrome/glaucoma, POAG, and cataract by HPLC.

Results

Differential and subtractive hybridizations, Northern blot analyses, quantitative RT-PCR and in situ hybridizations consistently demonstrated an up to 40-fold upregulation of A3-AR mRNA in the ciliary body, particularly in the nonpigmented ciliary epithelium, of all PEX eyes with and without glaucoma as compared to glaucomatous and non-glaucomatous control eyes. In contrast, the expression of AR subtypes A1, A2A and A2B was not significantly altered in PEX tissues. By immunohistochemistry, all AR could be immunolocalized to ocular tissues in a subtype-specific pattern; however, only the A3-AR showed increased immunoreactivity in the ciliary epithelium, the trabecular meshwork, and the iris vessels in PEX eyes as compared to control eyes. Mean aqueous adenosine levels were significantly increased in patients with PEX syndrome/glaucoma as compared to control patients and correlated with intraocular pressure levels.

Conclusions

Considering the known role of adenosine and its receptor A3 in modulation of aqueous humor secretion and intraocular pressure, an increased, probably hypoxia-induced adenosine release into the aqueous humor together with a selective upregulation and activation of the A3-AR may play an important role in intraocular pressure elevation and glaucoma development in PEX patients.